PROJECT SUMMARY Melanoma is deadly, has a rising incidence, and is the leading cause of death from skin diseases in the United States. The survival rate for advanced cases of melanoma is less than 15%. Our ongoing research on non- coding RNAs is motivated by the pressing need to understand the molecular mechanism of melanoma genesis and development. We originally reported that miR-211 expression is high in normal human melanocytes but is significantly reduced or absent in amelanotic melanoma cells, and its expression is also reduced in a high proportion of tissue samples from patients at different stages of melanoma progression. This miRNA is regulated by microphthalmia-associated transcription factor (MITF), and its ectopic expression in melanoma cells reduces cell growth and motility. These results suggest that miR-211 may have an important molecular function in human melanomas. Interestingly, recent results from our laboratory have shown that the depletion of miR-211 in normal human melanocytes and melanotic melanomas induces cell death and senescence, highlighting the potential role for miR-211 and its target genes in regulating melanocyte/melanoma biology. Nevertheless, the molecular mechanism by which miR-211 functions as a cell death or senescence trigger is not known. Based on our preliminary data, we hypothesize that miR-211 and its target genes regulate senescence and apoptosis in primary human melanocytes and melanoma cells. We propose the following Specific Aims to test our hypothesis. The focus of Specific Aim 1 is to determine the contribution of miR-211 to primary human melanocyte and melanoma cells in senescence and/or cell death. The focus of Specific Aim 2 is to determine miR-211 tumor forming potential in in vivo mouse models. At the end of this study, we will characterize the function and effect of miR-211 in melanocyte dedifferentiation and melanoma pathobiology.